A Phase 1, Open-label, Multicohort Study to Evaluate the Impact of Inhibitors and Inducers of Cytochrome P450 Enzyme (CYP)3A and/or P-glycoprotein (P-gp) on the Pharmacokinetics (PK) of Vesatolimod (VES) in Virologically Suppressed Adults With HIV-1 on Antiretroviral Therapy (ART)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 5
- 主要终点
- PK Parameter : %AUCexp of VES
研究概览
简要总结
The goal of this clinical study is to learn more about the impact of cobicistat (COBI) (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and strong cytochrome P450 enzyme [CYP]3A inhibitor), voriconazole (VOR) (strong CYP3A inhibitor), and rifabutin (RFB) (moderate CYP3A inducer) on the study drug, vesatolimod (VES), in people with HIV-1 on antiretroviral therapy (ART).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •On an antiretroviral therapy (ART) regimen for at least 6 consecutive months, with no change in the ART regimen within 2 months prior to screening. Permitted ARTs are as follows:
- •Cohort 1: A regimen of (bictegravir [BIC], dolutegravir [DTG], raltegravir [RAL], or doravirine [DOR]) plus Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Examples of acceptable regimens include BIC/emtricitabine/tenofovir, DTG/ abacavir (ABC)/3TC, DTG/3TC, DTG + emtricitabine/tenofovir, or DOR/3TC/tenofovir
- •Cohort 2: A DTG-based regimen is required (DTG/ABC/3TC), (DTG/3TC), or (DTG + NRTIs)
- •Plasma HIV-1 RNA levels less than 50 copies/mL at screening
- •Have normal hematologic function with an absolute neutrophil count greater than or equal to 1.5 × 10^9/L, platelets greater than or equal to 150 × 10^9/L; hemoglobin greater than or equal to 10.5 g/dL for females and greater than or equal to 11.5 g/dL for males
- •Clusters of differentiation (CD) 4 T cell count greater than or equal to 350 cells/μL
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN) and total bilirubin less than or equal to 1.5 mg/dL, or normal direct bilirubin and creatinine less than or equal to 1.25 x ULN
- •Have a calculated creatinine clearance (CLcr) of at least 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening and upon admission
- •Individuals assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception
- •Must be willing and able to comply with all study requirements and available to complete the study schedule of assessments
- •In the judgment of the investigator, be in good general health, based on review of the results from a screening visit
排除标准
- •Have received any study drug within 30 days prior to study dosing
- •Participation in any other clinical study (including observation studies) without prior approval from the sponsor is prohibited while participating in this study
- •Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual compliance or individual safety, or a positive drug or alcohol test at screening or baseline
- •No Evidence of chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] and/or positive HBV core antibody with positive reflex HBV DNA polymerase chain reaction (PCR)). Note: positive HBV core antibody with negative reflex HBV DNA PCR results are acceptable
- •No Evidence of active hepatitis C virus (HCV) infection (defined as positive hepatitis C antibody and HCV RNA above lower limit of quantitation). Note: positive anti-HCV antibody and negative HCV PCR results are acceptable
- •Acute febrile illness within 35 days prior to Day 1
- •Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study
- •Received any vaccine or immunomodulatory medication within 4 weeks prior to screening. Elective vaccination (eg, flu shot, hepatitis A or B vaccine) during the course of the study will require prior approval from the sponsor
- •Coronavirus disease of 2019 (COVID-19) vaccinations are allowed, with the requirement that they should not be administered within 7 ± 2 days of receiving VES
- •Have a history of any of the following:
- •Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria
- •Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
- •Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients
- •Autoimmune disease
- •Significant cardiac disease or a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years
- •Syncope, palpitations, or unexplained dizziness
- •Implanted defibrillator or pacemaker
- •Liver disease, including Gilbert syndrome
- •Severe peptic ulcer disease requiring prolonged (≥ 6 months) medical treatment
- •Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary
- •Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with individual treatment, assessment, or compliance with the protocol
- •For Cohort 1, individuals with CYP2C19 genotype of CYP2C19*2/*2, CYP2C19*2/*3, or CYP2C19*3/*3
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Cohort 1: Vesatolimod + Cobicistat + Voriconazole
Participants will receive a single dose of vesatolimod (VES) 2 mg on Day 1 of Period 1. In Period 2, participants will receive cobicistat (COBI) 150 mg once daily on Days 1 to 5 along with a single dose of VES 2 mg on Day 2. In Period 3, participants will receive a loading dose of voriconazole (VOR) 400 mg twice daily on Day 1, then VOR 200 mg twice daily on Days 2 to 6, and a single dose of VES 2 mg in the morning on Day 3. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1.
干预措施: Vesatolimod (Drug)
Cohort 1: Vesatolimod + Cobicistat + Voriconazole
Participants will receive a single dose of vesatolimod (VES) 2 mg on Day 1 of Period 1. In Period 2, participants will receive cobicistat (COBI) 150 mg once daily on Days 1 to 5 along with a single dose of VES 2 mg on Day 2. In Period 3, participants will receive a loading dose of voriconazole (VOR) 400 mg twice daily on Day 1, then VOR 200 mg twice daily on Days 2 to 6, and a single dose of VES 2 mg in the morning on Day 3. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1.
干预措施: Cobicistat (Drug)
Cohort 1: Vesatolimod + Cobicistat + Voriconazole
Participants will receive a single dose of vesatolimod (VES) 2 mg on Day 1 of Period 1. In Period 2, participants will receive cobicistat (COBI) 150 mg once daily on Days 1 to 5 along with a single dose of VES 2 mg on Day 2. In Period 3, participants will receive a loading dose of voriconazole (VOR) 400 mg twice daily on Day 1, then VOR 200 mg twice daily on Days 2 to 6, and a single dose of VES 2 mg in the morning on Day 3. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1.
干预措施: Voriconazole (Drug)
Cohort 2: Vesatolimod + Rifabutin
Participants will receive a single dose of VES 6 mg on Day 1. In Period 2, participants will receive Rifabutin (RFB) 300 mg once daily on Days 1 to 9 along with a single dose of VES 6 mg on Day 6. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1.
干预措施: Vesatolimod (Drug)
Cohort 2: Vesatolimod + Rifabutin
Participants will receive a single dose of VES 6 mg on Day 1. In Period 2, participants will receive Rifabutin (RFB) 300 mg once daily on Days 1 to 9 along with a single dose of VES 6 mg on Day 6. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1.
干预措施: Rifabutin (Drug)
结局指标
主要结局
PK Parameter : %AUCexp of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf, calculated as (\[AUCinf-AUClast\]/AUCinf)\*100. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES)
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
AUClast is defined as an area under the concentration versus time curve from time zero to the last quantifiable concentration. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : AUCinf of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
AUCinf is defined as an area under the concentration versus time curve extrapolated to infinite time, calculated as AUClast + (Clast/Lambda z). Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : Cmax of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Cmax is defined as the maximum observed concentration of drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : Tmax of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Tmax is defined as the time (observed time point) of Cmax. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : Clast of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Clast is defined as the last observed quantifiable concentration of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : Tlast of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Tlast is defined as the time (observed time point) of Clast. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : Lambda z of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Lambda z is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log concentration of drug versus time curve of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : t1/2 of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
t1/2 is defined as the terminal elimination half-life. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : CL/F of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
CL/F is defined as an apparent oral clearance. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
PK Parameter : Vz/F of VES
时间窗: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Vz/F is defined as an apparent volume of distribution of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)
时间窗: First dose date up to last dose date plus 30 days (up to 77 days for Cohort 1, and up to 54 days for Cohort 2)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can, therefore, be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. Adverse events may also include pretreatment or posttreatment complications that occur as a result of protocol-specified procedures, or special situations. TEAES included all AEs began on or after the study drug start date.
Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities
时间窗: First dose date up to last dose date plus 30 days (up to 77 days for Cohort 1, and up to 54 days for Cohort 2)
A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose at any time postdose. Data for participants with post baseline toxicity grade 1 or higher is reported.
次要结局
未报告次要终点